Gene transfer to hematopoietic stem cells (HSCs) remains an attractive approach for the treatment of numerous genetic disorders. Recent progress in the field of gene therapy has further raised the hope that patients afflicted with hemoglobinopathies such as β thalassemia and sickle cell anemia will benefit from novel therapeutic approaches. Transplantation of hematopoietic cells (HCs) modified with lentiviral vectors carrying the β-globin gene has resulted in long-term correction of several mouse models of hemoglobin disorders (Imren et al, Proc Natl Acad Sci USA. 2002; 99: 14380-14385; Malik et al., Ann NY Acad Sci. 2005; 1054:238-249; May et al, Nature. 2000; 406:82-86; Pawliuk et al, Science. 2001; 294: 2368-2371), but has led to transfusion independency in only one β thalassemic patient (Cavazzana-Calvo et al, Nature. 2010; 467:318-322).
The safety and utility of such treatments, however, are limited by difficulties in achieving sufficient numbers of transduced HSCs, either because of poor yields or functionality of the transduced cells. The use of different agents to enhance retroviral gene transfer has been reported, for example fibronectin (U.S. Pat. No. 5,686,278, Chono H et al. J Biochem. 2011 March; 149(3):285-92; Lee H J, Lee Y S, et al. Biologicals. 2009 August; 37(4):203-9), HIV Tat (Nappi F, et al. J Gene Med. 2009 November; 11(11):955-65), Vectofusin-1 (Fenard D, et al., Mol Ther Nucleic Acids. 2013 May 7; 2:e90), deoxynucleosides (Ravot E, et al., J Gene Med. 2002 March-April; 4(2):161-9), and cytokines (Geronimi F et al. Stem Cells. 2003; 21(4):472-80; Kiem H P, et al., Blood. 1998 Sep. 15; 92(6):1878-86).
There is thus a need for novel compounds and methods for enhancing gene transfer to HSCs, particularly in methods of gene therapy for the treatment or prevention of hematopoietic disorders.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.